The aim of the present work is to investigate the existence of epistatic interactions possibly influencing psychotropic agents' response between rs6740584 within Cyclic adenosine monophosphate Response Element Binding (CREB) and rs12775799 within cAMP response element-modulator (CREM) variants in bipolar disorder (BD) and major depressive disorder (MDD). All BD and MDD patients were administered with the Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HAMD) at baseline and at endpoint, respectively. A multiple regression model was employed to investigate the existence of possible epistatic interactions between the two variants and diverse clinical factors including drug response in affective disorders. No significant epistatic interaction was observed between rs6740584 within CREB and rs12775799 within CREM on both symptom improvement and other clinical factors in affective disorders. Our preliminary results suggest that no epistatic interaction between rs6740584 within CREB and rs12775799 within CREM should exist on clinical improvement and clinical factors in affective disorders.